Abstract
The existence of a hypothalamic gonadotropin-inhibiting system has been elusive. A neuropeptide named gonadotropin-inhibitory hormone (GnIH, SIKPSAYLPLRF-NH2) which directly inhibits gonadotropin synthesis and release from the pituitary was recently identified in quail hypothalamus. Here we identify GnIH homologs in the human hypothalamus and characterize their distribution and biological activity. GnIH homologs were isolated from the human hypothalamus by immunoaffinity purification, and then identified as MPHSFANLPLRF-NH2 (human RFRP-1) and VPNLPQRF-NH2 (human RFRP-3) by mass spectrometry. Immunocytochemistry revealed GnIH-immunoreactive neuronal cell bodies in the dorsomedial region of the hypothalamus with axonal projections to GnRH neurons in the preoptic area as well as to the median eminence. RT-PCR and subsequent DNA sequencing of the PCR products identified human GnIH receptor (GPR147) mRNA expression in the hypothalamus as well as in the pituitary. In situ hybridization further identified the expression of GPR147 mRNA in luteinizing hormone producing cells (gonadotropes). Human RFRP-3 has recently been shown to be a potent inhibitor of gonadotropin secretion in cultured sheep pituitary cells by inhibiting Ca2+ mobilization. It also directly modulates GnRH neuron firing. The identification of two forms of GnIH (RFRP-1 and RFRP-3) in the human hypothalamus which targets human GnRH neurons and gonadotropes and potently inhibit gonadotropin in sheep models provides a new paradigm for the regulation of hypothalamic-pituitary-gonadal axis in man and a novel means for manipulating reproductive functions.
Highlights
Gonadotropin-releasing hormone (GnRH) is the primary stimulator of gonadotropin secretion [1,2,3,4,5]
We identified the fully processed forms of gonadotropin-inhibitory hormone (GnIH) homologs in an extract of human hypothalamus by using an avian GnIH antibody-conjugated immunoaffinity column and mass spectrometry
The human genome database predicted the presence of an RFamide-related peptide (RFRP)-like peptide which has a C-terminus LPLRSamide motif, but this was not detected, possibly because of the difference in the C-terminal amino acid compared to avian GnIH, or because this peptide is not processed from the precursor
Summary
Gonadotropin-releasing hormone (GnRH) is the primary stimulator of gonadotropin secretion [1,2,3,4,5]. The recent identification of an avian hypothalamic dodecapeptide that inhibits pituitary gonadotropin release implies that such a factor might exist in vertebrates [9]. This factor, named gonadotropin-inhibitory hormone (GnIH), is synthesized in neurons of the paraventricular nucleus (PVN) in birds [9,10,11,12,13]. The GnIH neurons project to the median eminence, providing neuroanatomical infrastructure to allow secretion into the hypophysial portal system and regulate pituitary function [9,10,11,12,13]. While GnIH serves an important physiological role in birds [9,10,11,12,13,14,15,16,17,18,19], there has been limited evidence that the same is true for mammals
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